Project Summary This proposal describes the development of new methods for the preparation of 1,4-oxazin-2- one precursors and seeks to apply these intermediates to the construction of highly substituted pyridine products through a merged cycloaddition/cycloreversion process. The investigation of oxazinones will increase our understanding of the fundamental reactivity of this underutilized heterocyclic ring system. Additionally, pyridines are one of the most prevalent structures imbedded within biologically active molecules. Thus, new methods for the construction of pyridine motifs (especially those not easily prepared through condensation methods) is merited and is acutely significant to the biomedical sciences. Where possible, domino reaction processes are included that are economical with regard to time, are resource and cost efficient, and serve to rapidly generate molecular complexity. The proposed foundational experiments probe some of the potentially superior features of oxazinones relative to other [4+2]/retro[4+2] heterocycles used in pyridine synthesis. Applications directed toward the synthesis of biologically relevant pyridines are included in the proposal to showcase enabling features of the oxazinone scaffold: (1) a one-step multi component synthesis of a compound effecting neurite differentiation and (2) a unified synthesis strategy toward the guaipyridine alkaloids (including the anticancer compound cananodine and rupestines). A second objective of the proposal seeks to advance useful synthetic transformations starting from alkylidene 2,5-diketopiperazines. In particular, this proposal seeks to establish reliable methods for the synthesis of 1,2-carbonyl products and pyrrole- and dihydropyrrole-fused diketopiperazine structures. These products are valuable both as bioactive compounds or can be important precursors for the elaboration to more complex structures. The College of William & Mary does not offer a doctoral degree in chemistry (BS/MS only); accordingly, my research group is composed of undergraduate researchers (and one MS candidate). My current research program creates a rigorous environment for learning and enforces teaching and training in the one-on-one research experience. The proposed research would continue within this climate and is designed at an appropriate level for students to make progress. Support from the NIH would enable the research of 3-4 undergraduates and one Master's candidate for each year of the award.